Steroids



steroid-lacto-enol acylates which United ment-OT 2,740,782 STEROlDS John A. Hogg and Alan H. Nathan, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application October 24, 1952, Serial No. 316,801

15 Claims. (Cl. 260239.57)'

This invention relates to a novel class of steroid compounds, and is more specifically concerned with steroidlacto-enol acylates and with a process for the production thereof.

It is an object of the present invention to provide the novel class of steroids named herein as steroid-lacto-enol acylates. Another object is the provision of a process for the production thereof. Other objects willbe apparent to those skilledin the art to which this invention pertains.

The novel compounds of the present invention are may be represented by the following formula: I

24 QSC-OAc 20 22 St== I H Steroid-liictoenol acylate wherein Rand R1 are selected from the group consisting of hydrogen, hydroxy, ket'onic oxygen, and acyloxy, acyloxy being of the formula AcO, wherein Ac is the acyl radical of an organic carboxylic acid, particularly acids containing from one'to eight carbon atoms, inclusive, wherein R2 is selected from the group consisting of hydrogen, ketonic oxygen and acyloxy groups, acyloxy having the above definition and wherein the steroid nucleus may have the normal or allo configuration. In the above formulae, when a keto group is present at position three, a double bond may also be present at posi- 2,740,782 fiatented Apr. 3, 1956 tion four, in which case the indicated S-hydrogen atom is not present. When the three substituent is hydroxy or acyloxy, a double bond may also be present at the five position,'in which case the indicated 5-hydrogen atom is again not present. Moreover, the indicated steroid nucleus may also have other or additional double bonds located at other positions of the molecule and may likewise contain other substituents such as hydroxy, acyloxy, 'ketonic oxygen, halo, or the like at positions of the molecule other than those indicated.

According to the method of the present invention, a steroid 20-keto-2l-g lyoxalic acid possessing a l7-hydrogen and a ZI-hydrogen is contacted with an acylating agent to produce a steroid-lacto-enol acylate. The preferred embodiment of the invention resides in the preparation of the 2l-normethyl-23-acyloxy-17(20),22-choladieno-24(20)-lactones.

The novel compounds of the present invention are use ful precursors to steroids possessing a 17u-hydroxy group such as, for example, Kendalls compound E acetate l7a-hydroxy -21-acetoxy-4-pregnene-3,l 1,20-trione) or Kendalls compound F acetate (11fl,17a-dihydroxy-2lacetoxy-4-pregnene-3,20-dione). For example, treatment of 3a,23-diacetoxy-l 1-keto-21-normethyl-17(20) ,22-choladieno-24(20) -lactone (Example 1) -with perbenzoic' acid, as illustrated in Example 9, followed by treatment of the reaction product with sodium hydroxide, as described in Example 10', is productive of the known 3a,l7adihydroxypre'gnane-l1,20-dione which can be converted to cortisone acetate by the procedure of Kritchevsky et al., J. Chem. Soc. 74, 483 (1952). Similarly, other lacto-enolacylates of the present invention are converted to steroids possessing a 17u-hydroxy group.

The novel compounds of the present invention are well-defined, crystalline, stable, compounds which are insoluble in water. The unsaturation and oxygens present in the lactoneside chain render the compounds susceptible to reactions useful in the production of a wide variety of steroids. Thus, the lacto-enol acylates of the present invention are not only useful precursors to known and physiologically active steroids, but they are also useful in the preparation of entirely new types of steroids possessing a fifth ring attached to carbon atom 17.

In carrying out the process of the present invention, a 20-ketosteroid-2l-glyoxalic acid possessing a 17-hydrogen an'd'a 21-hydrogen is contacted with an acylating agent to produce a 2l-normethyl-23-acyloxy-17(20),22- choladieno-24(20)-lactone. The reaction is preferably conducted at a temperature between about room temperature, 'e. g., twenty degrees centigrade and the boiling point of the reaction mixture and in the presence of an organic solvent.

As disclosed previously and more fully illustrated by the formulae given above, steroid-2l-glyoxalic acids possessing a 20-keto group, a l7-hydrogen and at least one I hydrogen attached to carbon atom 21 are suitable startthe original groups may be readily restored, as by hydrolysis, for example.

The reaction temperature utilized in carrying out the process of the present invention may vary from about room temperature to the boiling point of the reaction Y mixture, with the reaction time necessary for optimum yield of product being somewhat dependent upon the temperature chosen. Temperatures around room temperature require relatively long reaction times with one to two days being not uncommon, whereas when the reaction is carried out at the. boiling point of the reaction mixture, less than an hour of reaction time is sometimes required to obtain a satisfactory yield of product.

Acylating agents most frequently employed in carrying out the process of the present invention are the anhy-' drides of organic carboxylic acids, particularly anhydrides of carboxylic acids containing from two to eight carbon atoms, inclusive. When a 23- formyloxy group is desired, formic acid is the preferred acylating' agent. While organic carboxylic acid anhydrides and formic acid are preferred acylating agents in the process of the present invention, other acylating agents such as, for example, ketene or other like ketenes, isopropenyl acetate or other isopropenyl acylate, or the like, may also be used.

The process of the present invention is conveniently carried out in an organic solvent which is substantially non-reactive under the conditions of reaction. Reaction solvents which may be used include aliphatic acids such as, for example, acetic, propionic, butyric, or the like, pyridine, picoline, collidine, benzene, toluene, an excess of the acylating agent, mixtures of one or more of the above, and others.

Isolation of the thus-produced 2l-normethyl-23-acyloxy-17(20),22-choladieno-24(20)-lactone is conveniently achieved by distillation of the reaction solvent and the excess acylating agent from the reaction mixture, leaving a residue consisting essentially of the lacto-enol acylate. Alternatively, the reaction product can be isolated by mixing the reaction mixture with water, thus' precipitating the desired product, followed by filtration of the precipitated product. Purification of the reaction product may be accomplished by recrystallization of the reaction product from a solvent such as, for example, ether, ethyl acetate, ethanol, methanol, pentane, hexane, chloroform, acetic acid, mixtures of these, or the like.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.

PREPARATION 1.SonruM ENOLATE on zl-nrnoxxoxsryr- 30z-HYDROXYPREGNANE-1 1,20-DIQNE To a mixture of 3.4 milliliters of a 3.4 N solution of methanolic sodium methoxide, 19.5 milliliters of dry benzene and 0.5 milliliter of absolute ethanol, said mixture having been distilled until approximately eight milliliters of distillate had been collected and the mixture then cooled, was added 2.3 milliliters of ethyl oxalate with stirring followed by a solution of 3.32 grams (0.01 mole) of 3e-hydroxypregnane-l1,20-dione in .a mixture of thirty milliliters of dry benzene and five milliliters of absolute ethanol. The reaction mixture was stirred for 85 minutes during which time some solid material precipitated. Sixty milliliters of anhydrous ether was then added thereto and the whole stirred for an additional hour, whereafter an additional 100 milliliters of anhydrous ether was aded thereto. The ivory colored sodium enolate of 21-ethoxyoxalylr3e-hydroxypregnane, 11,20-dione thus precipitated was filtered, washed with ether and, after drying in a vacuum desiccator over Drierite (anhydrous calcium sulfate), was found to weigh 3.65 grams, a yield of 85 per cent of the theoretical. The product melted above 250 degrees centigrade.

A. ZI-GLYOXALIC ACID OF 3a-H'YDROXYPREGNANE- 11,20-DIONE Five hundred and sixty milligrams of the sodium enolate of 21-ethoxyoxalyl-3a-hydroxypregnane-l1,20- dione was dissolved in a solution of seventy milligrams of potassium hydroxide in fifteen milliliters of a solution composed of equal parts of water and alcohol, whereafter the Whole was heated for fifteen minuteson a steam bath.

The cooled solution was then filtered and upon acidification there was slowly deposited 345 milligrams of a white crystalline precipitate of the 21-glyoxalic acid of 3a-hydroxypregnane-l1,20-dione. The infrared analysis of said compound in solution (chloroform) verified the structure proposed.

Analysis.Per cent calcd. for C23H320s: C, 68.29; H, 7.97. Found: C, 68.12; H, 7.87.

PREPARATION 2.--SonnJM ENOLATE OF 21-nrnoxvoxxrrr- 3B-HYDROXYPREGNANE-1 1,20-DIONE Using essentially the procedure described in Preparation 1, S S-hydrOXypregnane-I1,20-dione is converted to the sodium enolate of 21-ethoxyoxalyl-3fi-hydroxypregnane-11,20-dione by reaction with ethyl oxalate and sodium in absolute ethanol.

A. fll-GLYOXALIC ACID OF SB-HYDROXYPREGNANE- 11,20-DIONE In the same manner as described in Preparation 1A, the 2l-glyoxalic acid of 3 3-hyd roxypregnane-11,20-dione is prepared from the sodium enolate of 2l-ethoxyoxalyl- 313-hydroxypregnane-11,20-dione by reaction with sodium hydroxide in alcohol and water and thereafter acidifying the reaction mixture.

PREPARATION 3.SoDroM ENOLATE on ZI-ETHOXYOXALYL- 1 l-KETOPROGESTERONE To a mixture of 3.4 milliliters of a 3.4 N methanolic sodium methoxide solution, 0.45 milliliter of absolute ethanol, and twenty milliliters of dry benzene, said mixture previously having been distilled until eight milliliters of distillate had been collected, and then cooled, was added 2.3 milliliters of ethyl oxalate and a solution of 3.28 grams of ll-ketoprogesterone in 38 milliliters of dry benzene. The solution became turbid and a yellow precipitate formed. The reaction mixture was stirred for ninety minutes, milliliters of ether was then added thereto, and stirring was continued for sixty minutes, whereafter a 130-milliliter portion of ether was added thereto. The thus-formed yellow precipitate of the sodium enolate of 21-ethoxyoxalyl-1l-ketoprogesteronc was filtered, washed with several fifty-milliliter portions of ether, and after drying found to weigh 3.65 grams. The ether wash contained 0.54 gram of unreacted 11- ketoprogesterone. The yield of the sodium enolate of 2l-ethoxyoxalyl-1l-ketoprogesterone was 81 per cent of the theoretical or practically quantitative calculated on the reacted ll-ketoprogesterone.

A. 2 1-GLYOX ALIC ACID OF ll-KETOPROGESTERONE In the same. manner as described in Preparation 1A, the 21-glyoxalic acid of ll-ketoprogesterone is prepared and isolated by treatment of the sodium enolate of 21- ethoxyoxalyl-ll-ketoprogesterone with potassium hydroxide in alcohol and water, thereafter acidifying the mixture with dilute hydrochloric acid and then filtering the precipitated 2l-glyoxalic acid of ll-ketoprogesterone.

PREPARATION. 4.SonrUM ENOLATE 0F ZI-ETHOXYOXALYL- I Im-HYDROXYPROGESTERONE Three and three-tenths (3.3) grams of lla-hydroxyprogesterone [Peterson and Murray, I. Am. Chem. Soc. 74, 1871 (1952)] was dissolved in a solution of 0.25

, gram of sodium in eighty milliliters of absolute ethanol,

prepared by the reaction of the sodium enolate of 21- ethoxyoxalyl-lla-hydroxyprogesterone with sodium hydroxide in a mixture of alcohol and water and thereafter acidifying the reaction mixture with dilute hydrochloric acid.

PREPARATION 5.-SODIUM,ENOLATE 0F ZI-ETHOXYOXALYL- One hundred and forty-four (144) milligrams (6.25 millimoles) of sodium was dissolved in five milliliters of absolute ethanol under an atmosphere of nitrogen and to this solution were added eight milliliters of benzene and 0.8 milliliter (0.9 gram; 6.15 millimoles) of ethyl oxalate. The mixture was cooled in an ice-water bath and a solution of 1.99 grams (6.03 millimoles) of 11p;- hydroxyprogesterone dissolved in five milliliters of absolute ethanol and mixed with 25 milliliters of dry benzene was added in a slow stream to the stirred solution. The reaction mixture was stirred at room temperature for 2.5 hours, at the end of which time a 100-milliliter portion of ether was added, followed by another 100- milliliter portion of ether one hour later. The thusproduced pale yellow precipitate of the sodium enolate of 2l-ethoxyoxalyl-1lfi-hydroxyprogesterone was filtered and washed with ether. The yield was 1.68 grams (62 percent). 1 J

A. 21-GLYOXALIC ACID on llfi-HY-DROXY- PROGESTERONE In the same manner as described, in Preparation 1A, the 2l-glyoxalic acid of llfi-hydroxyprogesterone is prepared by reacting the sodium enolate of 2l-ethoxyoxalylllfl-hydroxyprogesterone with sodium hydroxide in water and alcohol and thereafter acidifying the reaction mixture.

In the same manner as described in Preparations 1' through 5, the 2l-ethoxyoxalyl derivatives of the following compounds are prepared by reacting the following compounds with ethyl oxalate in the presence of base: progesterone, 3aand 3B-hydroxy'5-pregnene-20-one, 3aand 3fi-hydroxypregnane-20-one, pregnane-3,20-dione, 1104- and 11,B-hydroxypregnane-ZO-one, pregnane-3,1l,20-' trione, 3a,11a-, 3u,llfl-, 3B,11a.- and 3,8,11,8-dihydroxypregnane-ZO-one, 11aand 1lfl-hydroxypregnane3,20- dione, the allo steroids corresponding to these and other like steroids, organic carboxylic acid esters of the foregoing hydroxysteroids, and the like.

The 2l-glyoxalic acids of the above-named compounds and others are prepared by reacting the 21-ethoxyoxalyl derivatives of the above-named compounds or the like with an alkali-metal hydroxide or similar hydrolyzing agent in alcohol and water or other suitable hydrolyzing solvent and thereafter acidifying the reaction mixture with dilute acid in a manner similar'to the method described in Preparation 1A.

Example 1.--3a,23 diacetoxy 11 keto 21 nor methyl-17(20) ,22-choladieno-24(20) -lact0ne A mixture of 2.918 grams of '3a-hydroxypregnane- 11,20-dione-2l-glyoxalic acid, 3.8 milliliters of a one Normal solution of hydrogen bromide in acetic acid, fifteen milliliters of acetic anhydride, and fifteen milliliters of glacial acetic acid was heated for one-half hour at the reflux temperature of the, reaction mixture, whereafter the volatile components were removed by distillation at reduced pressure. The distillation residue was triturated with water until crystallization occurred. The crude crystalline mass was filtered and Washed with water and thereafter dried. The yieldof dry 3a,23- diacetoxy l1 keto 21 normethyl l7(20),22 choladieno-24(20)-lactone, melting at about 145 to 155 degrees centigrade with softening at 130 degrees, was 3.395 grams, representing a quantitative yield. Several recrystallizations from methanol or a mixture of ether and Skellysolve B" hexane hydrocarbons in the propor tion of about thirty milliliters of solvent per gram ofproduct raises the melting point to 210 to 210.5 degrees Example 2.-3u,23 diacetoxy 11 keto 21 nor methyl-1 7(20) ,22-ch0ladieno-24 (20) -lact0ne A solution of 685 milligrams of 3u-hydroxypregnane- 11,20-dione-21-glyoxalic acid in 6.85 milliliters of pyridine and 6.85 milliliters of acetic anhydride was maintained at room temperature for twenty hours, whereafter the whole was poured into sixty milliliters of ice and water. After the excess acetic anhydride had hydrolyzed, the precipitated 3oz,23-diacetoxy-l1-keto-21-normethyl- 17(20),22-choladieno-24(20)-lactone was filtered, washed with water and thereafter dried, first in the air and then in a vacuum oven. Infrared absorption analysis confirmed the identity of the product.

Treatment of 3a,23-diacetoxy-1l-keto-2l-normethyl- 17(20),22-choladieno-24(20)-lactone .or other 304,23- diacyloxy homologues thereof with perbenzoic acid according to the method given in Example 9 and treating the reaction product with aqueous sodium hydroxide according to the method described in Example 10, is productive of 3a,l7oz-dihydroxypregnane-11,20-dione.

Example 3.313,23 diacetoxy 11 keto 21 nor methyl-I 7(20) ,22-choladieno-24 (20) -lact0ne In the same manner as described in Example 1, 313,23- diacetoxy ll -keto 21 normethyl l7(20),22 choladieno-24(20)-lactone is preparedby reacting 3,B-hydroxypregnane-l1,20-dione-21-glyoxalic acid with acetic anhydride in glacial acetic acid and in the presence of anhydrous hydrogen chloride.

Isolation of the thus-produced 36,23-diacetoxy-ll-keto- 21 normethyl l7(20),22 choladieno 24(20) lactone is achieved by distillation of the reaction mixture and crystallizing the distillation residue from methanol.

Treatment of 35,23 diacetoxy 11 keto 21 normethyl-l7(20),22-choladieno-24(20)-lactone or other 35,23-diacyloxy homologues thereof with perbenzoic acid and thereafter with aqueous sodium hydroxide is productive of 3/3,l7a-dihydroxypregnane-1l,20 dione.

Example 4.3a,23 diacetoxy 11p hydroxy 21 normethyl-1 7 (20) ,2Z-choladieno-24 (20) -lact0ne Example 5.-3a,11a,23 triacetoxy 21 normethyl 17(20),22-choladien0-24(20)-lact0ne In the same manner as described in Example 4, 3a,11ct,23 triacetoxy 21 normethyl l7(20),22

choladieno-24(20)-1actone is prepared by substituting 31!,110: dihydroxypregnane 20 one 21 glyoxalic acid for 3a,l1fi dihydroxypregnane 20 one 21 glyoxalic acid as starting material in the reaction.

Example 6.-3,11 diketo 21 normethyl 23 acetoxy 4,1 7 (20) ,22-ch0latrien0-24 (20 -lactone In the same manner as described in Example 2, 3,11- diketo 21 normethyl 23 acetoxy 4,17 (20),22 cholatrieno-24(20)-lactone is prepared from the 21- glyoxalic acid of ll-ketoprogesterone by treatment of the latter with acetic anhydride in pyridine.

Substitution of propionic anhydride for the acetic anhydride of the example is productive of 3,11-diketo-21- normethyl 23 propion'oxy 4,.17-'t2o- .,221- cholatrieno. 24(20) -lactone.

Example 7.--3-ket0-1 1 a,2 3-diacet0xy-21 -nrmethyl- 4,17 (20),22-ch0latrieno-24 (20) -luct0ne In the same manner as described in Example 2, 3-keto- 1la,23 diacetoxy 21 normethyl 4,17(20),22 cholatrieno-24(20)-lactone is prepared from the 21-glyoxalic acid of lla-hydroxyprogesterone by treatment of the latter with acetic anhydride in pyridine.

Similarly, 3-keto-11p-hydroxy-21-normethyl-23-acetoxy- 4,l7(20),22-cholatrieno-24(20)-lactone is prepared by substituting the 21-glyoxalic acid of 11 fl-hydroxyprogesterone for the 21-glyoxalic acid of llwhydroxyprogesterone in the reaction described above.

Substitution of propionic anhydride for the acetic anhydride of the example is productive of 3-keto-11wacetoxy-21-normethyl-23-propionoxy-4,17(20) ,22-cholatrieno- 24(20)-lactone.

Example 8 .3 -ket0-I 1 fi-hydroxy-Zl -normeth yl-23 -acctoxy-I 7 (20 ,22-cIzoladieno-24 (20 Jaclane and 3 -keto- 1111,23 diacetoxy 21 normethyl I7(20),22 choladieno-24(20) -lact0ne In the same manner as described in Example 2, 3-keto- 11 8 hydroxy 21 normethyl 23 acetoxy 17(20),22- choladieno-24(20)-lactone is prepared from the 2l-glyoxalic acid of 11fl-hydroxypregnane-3,ZO-dione by reaction of the latter compound with acetic anhydride in pyridine.

Similarly, by substituting the 21-glyoxalic acid of 11ahydroxypregnane-3,20-dione for the 2l-glyoxalic acid of l1fi-hydroxypregnane-Ii,20-dione in the above-described reaction, 3 keto 11ct,23 diacetoxy 21 normethyl 17(20),22-choladieno-24(20)-lactone is prepared.

In the same manner as described in Examples 1 through 8, the 23-acyloxy homologues of these and other steroids wherein the acyloxy group has the formula AcO, Ac being the acyl radical of an organic carboxylic acid such as, for example, formic, acetic, propionic, butyric, valeric, hexanoic, heptanoic, octanoic, benzoic, or the like, are prepared by reacting the anhydride of the selected organic carboxylic acid, or with formic acid if formyloxy is the desired acyloxy radical, with the 21- glyoxalic acid of the selected steroid in a solvent such as, for example, pyridine, collidine, picoline, acetic acid, propionic acid, or the like.

21-glyoxalic acids of other steroids which may be used in carrying out the process of the present invention include the 2l-glyoxalic acids of progesterone, llaand 1 1,B-hydroxypregnane-ZO-one, l 1 fl-hydroxyprogesterone, 3aand 3fi-hydroxypregnaner20-one, pregnane-3,20'- dione, pregnane-3,1l,20-trione, 3aand 3fi-hydroxy-5-pregnene-20-one, 3fi,l1aand 3,8,1lfl-dihydroxypregnane-ZO- one, 1lohydroxypregnane-3,ZO-dione, the allo steroids corresponding to these and other like steroids, organic carboxylic acid esters of the foregoing hydroxysteroids, and others, all of which are prepared in the manner indicated in the foregoing preparation, i. e., reacting the selected starting steroid with an ester of oxalic acid in the presence of an alkali-metal base or alkalintetal alkoxide in a convenient organic solvent, followed by saponification in alkali solution and treatment with an acid to yield the corresponding 2l-glyoxalic acid.

Representative other compounds prepared from these 21-glyoxalic acids in the manner described in Examples 1 through 8 include: l1a,23-diacetoxy-2l-normethyl- 17 (20) ,22-choladieno-24 20 -lactone, llfl-hydroxy-Zlnormethyl 23 acetoxy l7( 20),22 choladieno 24 (20) lactone, 1113 hydroxy 3 keto 21 normethyl 23 acetoxy 4,l7( 20),22 cholatrieno 24(20) lactone, 311,23 diacetoxy 21 normethyl 17=(20),22 choladieno 24(20) lactone, 3 8,23 diacetoxy 21 normethyl l7(20),22 choladieno 24(20) lactone, 3 keto 21 normethyl 23 acetoxy 17 (20),22 choladieno- 241(20) -lactone, 3,11 diketo 21 nor.m e1h.- yl 23 acetoxyl7(-20),22- choladieno, 24(20) lac tone, 3.0:,23. diacetoxy' 2'1 normethyl 5,17(20),,2,2, cholatrieno 24(20) lactone, 3 3,23 diacetoxy 21 normethyl 5,17(20),22 cholatrieno 24(20) lactone, 3 5,lla,23 triacetoxy 21 normethyl 17(20) .22 choladieno 24(20) lactone, 3fi,11;3,23 triacetoxy 21 normethyl 17(20),22 choladieno 24(20) lactone, 11,23 diacetoxy 3 keto 21 normethyl 17(20), 22 choladieno 24(20) lactone, 311,23 dipropioncxy l1 keto 21 normethyl 17(20),22 choladieno 24(20) lactone, 319,23 dibutyroxy 11 keto 21 normethyl l7(20),22 choladieno 24(20) lactone, 3 keto 21 normethyl 23 valeroxy 17(20),22 choladieno 24(20) lactone, 3,11 diketo 21 normethyl 23 hexanoyloxy 17(20),22 choladieno 24 (20) lactone, 11B hydroxy 3 keto 21 normethyl 23 heptanoyloxy 17(20),22 choladieno 24(20) lactone, 311,23 dioctanoyloxy 21 normethyl 5,17 (20),22 cholatrieno 24(20) lactone, 35,23 diformyloxy 21 normethyl 5,17 (20),22 cholatrieno 24(20) lactone, 3a,11a,23 triformyloxy 21 normethyl 17(20),22 choladieno 24(20) lactone, 3a., 23 dibenzoyloxy 11p hydroxy 21 normethyl 17 (20),22 choladieno 24(20) lactone, 3B,11a,23 triformyloxy 21 normethyl 17(20),22 choladieno 24(20) lactone, 318,23 diformyloxy 11p hydroxy 21 normethyl 17(20),22 choladieno 24(20) lactone and others.

Contacting one of the above-named steroids, or the like, in an organic solvent, e. g., chloroform, with an organic peracid, e. g., perbenzoic acid, or hydrogen peroxide, followed by treatment with an aqueous or alcoholic alkali-metal hydroxide, e. g., sodium hydroxide, introduces a l7tz-hydroxy group into, the steroid nucleus. The following examples are illustrative.

Example 9.3 (1,23 -diacet0xy-1 I -ket0-1 7 (20 -0xia'0-2I normethyl-22-ch0len0-24 (20 -lact0ne A solution of 0.8 gram of 3a,23-diacetoxy-11-keto-21- normethyl- 1 7 (20) ,22-choladieno-24 20 -lactone, melting at 210 to 210.5 degrees centigrade, obtained according to the method described in Example 1, dissolved in twenty milliliters of chloroform, was mixed at room temperature with twenty milliliters of a solution of perbenzoic acid in benzene containing 61 milligrams of perbenzoic acid per milliliter. The consumption of the perbenzoic acid was followed by iodornetric titration of aliquot samples taken from time to time from the reaction mixture. After about eight hours one molar equivalent of perbenzoic acid had been consumed and the consumption of perbenzoic acid thereafter essentially ceased. The reaction mixture was washed with successive portions of a dilute aqueous sodium bisulfite solution, sodium bicarbonate solution, and finally with water. After drying the benzenechloroform layer with anhydrous sodium sulfate and thereafter distilling the solvent therefrom, an amorphous white powdery residue was obtained which crystallized upon trituration with 25 milliliters of denatured alcohol. The alcohol was then heated to boiling to dissolve all of the crystalline residue and was thereafter cooled, whereupon 437 milligrams, a yield of .66 percent of the theoretical, of white needles of 3,23-diacetoxy-11 keto-17(20)- oxido-Z1-normethyl-22-choleno-24(20)-lactone, melting at 179.5 to 181.5 degrees centigrade, crystallized there-- from. Furtherrecrystallization of these crystals from alcohol gave product melting at 191 to 192 degrees centigrade (corrected).

Analysis.Percent calcd. for CzvHarOe: C, 66.65; H, 7.04. Found: C, 66.85; H, 6.86.

Example 10.-3a,17a-dihydr0xypregnane-11,20-di0ne A solution of fifty milligrams of 3a,23.-diace toxy- 11- keto 17(20) oxido 21 normethyl 22 pholeno 24(20)-lactone, obtained according to the method devac '10 scribed in Example 9, dissolved in two milliliters of 95. t H percent ethanol, was heated to boiling and contacted while hot with about 0.5 milliliter of one Normal aqueous sodium hydroxide. The solution was then heated at the boiling point of the reaction mixture for five minutes and thereafter maintained at room temperature for sixteen hours. The solution was made acidic with dilute hydrochloric acid, whereupon 42 milligrams of a white solid precipitated. These crystals were dissolved in two milliliters of a one Normal sodium hydroxide solution and heated on a steam bath for about five minutes whereupon 15.2 milligrams of white crystals of 3a,l7a-dihydroxypregnane-11,20-dione, melting at 195.5 to 199 degrees centigrade, precipitated. Recrystallization of these crys- 7 A 3,23 diacetoxy 21 normethyl 7 ,22 tals from dilute methanol raised the melting point of the 1 h l di 24(20)-lactone of the formula:

product to 203 to 204.5 degrees centigrade, which was not depressed upon taking a mixed melting point with.

authentic 3a,17a-dihydroxypregnane-11,20-dione. The ing frared absorption spectrum also confirmed the identity of the product. 20

. It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in theart, and the invention is therefore to be limited only by the scope 25 of the appended claims. 0 1

We claim: JL

1. A process for the production of 3a,23-diacetoxy-11- keto 21 normethyl 17 (20),22 eholadieno 24(20) i lactone which comprises: contacting 3a-hydroxypregnane- 311,23 dIaCFtOXY 11 keto 21 normethyl 17 11,20-dione-21-glyoxa1ic acid with acetic anhydride in an (2 m clwlaldmno (2 .1 nqq t e ormu organic solvent and at a temperature between about twen- I w ty degrees centigrade and the boiling point of the reaction vmixture to produce 3ct,23-diacetoxy-11-keto-21- normethyl-17(20),22-choladieno-24(20)-lactone. a

2. A process for the production of 35,23-diacetoXy-11- Cm I keto 21 -normethyl l7(20),22 choladieno 24(20) lactone which comprises: contacting 3fl-hydroxypregnane- 0 11,20-dione glyoxalic. acid with acetic anhydride in an 0H; organic solvent'and at a temperature between about twen- 40 ty degrees centigrade and the boiling point of the reaction mixture to produce;3fl,23 diacetoxy l1 keto 21 o normethyl l7(20),22 choladieno 24(20) lactone. OHr--O- 3. A process for the production of 3a,11a,23-triacetoxy- 21 normethyl l7(20),22 choladieno 24(20) lactone which comprises: contacting 3a,lla-dihydroxypregnane- 20-one-21-g1yoxalic acid with acetic anhydride in an organic solvent and at a temperature between about twenty degrees centigrade and the boiling point of the reaction mixture to produce 311,11a,23-triacetoxy-2l-normethyl-l7- (20) ,22-choladieno-24 (2O -lactone.

4. A process for the production of 3-keto-11fl-hydroxy- 21-normethyl-23 -diacetoxy- 17 (20 ,22-choladieno-24 (20) 0- lactone which comprises:' contacting llfl-hydroxypregnane-3,20-dione-2l-glyoxalic acid with acetic anhydride in an organic solvent and at a temperature between about twenty degrees centigrade and the boiling point of the E reaction mixture to produce 3 keto 11p hydroxy 21 normethyl 23 diacetoxy l7(20),22 choladieno 24 Y (20)-lactone :10. 3u,11m,23 triacetoxy 21 normethyl l7(20),22-

A Process the Production of 3,11'dikem'21' choladieno-24(20)-lactone of the formula: normethyl 23 acetoxy 4,17(20),22 cholatrieno 24 (20)-lactone which comprises: contacting 11 ketoproges- 0 terone-21-glyoxalic acid with acetic anhydride in an organie solvent and at a temperature between about twenty degrees centigrade and the boiling point of the reaction CH; mixture to produce 3,11 diketo 21 normethyl 23 o acetoxy 4,17 (20);22 cholatrieno 24(20) lactone. 7o 0H=Lo- 6. A 3,23 di lower acyloxy 21 normethyl 17 (20),22 choladieno 24(20) lactone, wherein the acyloxy groups are of the formula AcO, Ac being the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive of the formula:

9. 313,23 diacetoxy 11 keto 21 normethyl 17 {20),22 choladieno 24(20) lactone of the formula:

O om-1L0 .;1 11. 3 keto 11B hydroxir 3 21 normethyl 23 acetoxy 17(20),22 choladieno 24(20) lactone of the formula:

12. 3,11 diketo 21 normethyl 23 acetoxy 4,17 (20),22 cholatrieno 24(20) lactone of the formula:

13. A process for the production of a 21 normcthyl 23 acyloxy 17 (20),22 choladieno 24(20) lactone wherein the acyloxy'group is AcO, Ac being the acyl radical ofa hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, which comprises contacting a 20-keto-2lglvoxalic acid steroid having the formula:

d -x s ic iok snaas a ia 'la w rl u cflhai rmiila, z i w-ms the W1 ad a Qi n ani AQtw fi i, i carboxylic acid: containing from one. to eight. carbon 7 atorns, inclusive andwherein R2 13. selectedffrom, the,

groupjconsi stingo f hydrogen, hydroxy, ketonic oxygen and. an acylogry group whereinthe acyloxy groupis AcO,

Ac being the acy l radical of an organic carboxylic acid coutaini ng from one. toeight carbon, atoms, defined as above with an acylating agent, selectedfrom the group- DAc wherein R i s selected froni the group consisting of ketoni q oxygen, and an acyloxy group having the formula AcO, Ac licingutheacyl radical of'a hydrocarbon carboxylic acid containing fro n one to eight carbonaton s, inclusive, andwherein Rzis selected from the group consisting of hydrogen, ketonic oxygen, hydroxy, and acyloxy' as No references cited. 

15. A 21 - NORMETHYL - 23 - LOWER - ACYLOXY - 17(20), 22- CHOLADIENO - 24(20) - LACTONE REPRESENTED BY THE FOLLOWING FORMULA: 